The medium is susceptible to the cavitation phenomenon. The cavitation is the creation or formation of vapor bubbles in a medium in a region where the pressure falls below a pressure threshold, said threshold corresponding to the called cavitation level. Additionally, said pressure threshold may be the vapor pressure of said medium or higher to this vapor pressure. During cavitation, the cavitation bubbles may dynamically oscillate. Then, the cavitation bubbles may rapidly collapse, producing a localized shock wave in the medium, an increase of local temperature, some mechanical stresses and/or chemical effects. The cavitation may be produced when the medium comprises some nuclei. The cavitation may be also produced by adding microbubbles or bubbles inside the medium, or by adding ultrasound contrast agents.
Moreover, it is well-known to use ultrasound waves for delivering a substance inside a region of interest. More precisely, it is known to generate and to focus a single ultrasound beam on a point inside a medium (i.e. a target point), so that to produce cavitation inside a region around said target point and to make a delivery compound to switch from a holding state in which the substance is held by the delivery compound, to a releasing state in which the substance is released by the delivery compound.
The substance may be a chemical substance, a radioactive substance, a color substance, a gene, a plasmide or a drug. The substance may be held by a delivery compound in a holding state when there is no cavitation inside the medium in near proximity of the delivery compound. In that state, the substance is not free to move into the medium independently of the delivery compound, and is not able to be active and to react with another substance inside the medium. The substance is released by the delivery compound in a releasing state when there is cavitation inside the medium in near proximity of the delivery compound. In that state, the substance is free to move into the medium independently of the delivery compound, and is able to be active and to combine with other substance.
The delivery compound is therefore sensitive to the cavitation, and releases the substance if it is in near proximity of cavitation bubbles. Near proximity means a distance between the delivery compound and a cavitation bubble smaller than 1 mm. If cavitation bubbles are localized inside a region of interest of the medium, i.e. if the cavitation occurs inside said region of interest, the delivery compound releases the substance substantially inside said region of interest. The substance is transported through the medium to the localized region of interest inside said medium and is released inside said localized and reduced region of interest. The delivery compound may be considered as a means of transportation and delivering for the substance inside the medium from any origin to the localized region of interest. Many delivery compounds are well-known. It may be a microparticules or nanoparticle, and for example a liposome, a micelle, or the like.
In another case, the substance may be released without a delivery compound inside a region of interest of the medium when there is cavitation inside said region of interest of the medium. Indeed, the substance may be sensitive to the cavitation.
As used herein, the term “particles” refers to an aggregated physical unit of solid material. The particles according to the invention may be micro- or nanoparticles. Microparticles are understood as particles having a median diameter d50 ranging from 500 μm to 1 μm and more preferably from 100 μm to 1 μm, and most preferably from 10 μm to 1 μm. Nanoparticles are understood as particles having a median diameter d50 inferior to 1 μm and notably ranging from 0.1 μm and 0.01 μm. As used herein, the term “median diameter d50” refers to the particle diameter so that 50% of the volume or of the number of the particles population have a smaller diameter. More specifically, the microparticles or nanoparticles may be microspheres or microcapsules, nanospheres or nanocapsules respectively, containing an active substance.
In particular, the generation of ultrasound intensity (i.e. ultrasound pressure) localized in a region of interest, for example a cancer tumor is well-known and very interesting. Indeed, it may be used for drug delivering inside a body. The body is for example an animal or a human body. The drug may be delivered inside the body preferentially to a predetermined region inside the body (i.e. the “region of interest”), and less somewhere else. Moreover, the needed quantity of drug for the treatment of the predetermined region is greatly reduced compared to known methods without such delivery method.
Thus, such application has a great interest for the treatment of cancer tumor. The drug is released by the delivery compound only inside the tumor. The cancer tumor may be treated without releasing the drug everywhere inside the body. The drug is often harmful and toxic for organs inside the body. Many undesirable side effects of a global treatment of the body may be therefore avoided.
Furthermore, the generation of ultrasound intensity is used for sonoporation or transfection applications, wherein plasmids are transferred inside a cell. For these applications, the substance comprises at least a plasmid. The substance may be a plasmid, a gene, or a plasmid graft on a liposome. The focal point P is positioned near at least one cell. The cavitation phenomenon releases the substance and simultaneously opens the cell to transfer the plasmid inside said cell.
For generating ultrasound intensity inside a region of interest of a medium, it is known to use a device which comprises a transducer to generate and to focus a single ultrasound beam on a target point inside a medium, so that to produce cavitation inside a region around said target point. This method is satisfactory, but still need to be improved.
In the document WO2008/018019, it is disclosed a device which comprises two transducers generating two ultrasound beams which are focused. However, the position of the transducers and the signals sent to the transducers are not optimized. The beams are not accurately superposed on the acoustic transducers focal points.
Indeed, it is important to take into account that each transducer has an acoustic focal distance that is a distance between the transducer surface and an acoustic focal point where the ultrasound pressure in the medium has the greatest amplitude. However, the transducers have a nonlinear behavior. The acoustic focal distance depends on the signal amplitude provided to the transducer, and, for example, the acoustic focal distance decreases for high amplitude signals.
The acoustic focal point of focused beam is the effective acoustic focal point, that is to say the point into the medium where a pressure reaches a maximum value, i.e. where the acoustical power or intensity inside the medium has a maximum value.
The transducers also have a geometric focal point. These geometric focal points are localized at a predetermined geometric focal distance from a surface of each transducer, said surface producing the ultrasound wave into the medium. The geometric focal point is defined by the geometrical properties of the transducer. For example, for a transducer having a semi-spherical surface, the geometric focal distance is substantially equal to the radius of curvature of said transducer's surface.
The acoustic focal point is located near the geometric focal point for a small amplitude signal provided to the transducer. Due to the nonlinear behavior of the transducer, this acoustical focal point is moving towards the transducer's surface with respect to increase of the signal amplitude.
A first transducer receiving a first signal of a first amplitude so that to generate a first beam of a first ultrasound wave inside a medium towards a first beam direction produces a first zone of high pressure inside said medium, i.e. a first zone of maximum acoustic power or intensity. The first zone is typically centered on the first acoustic focal point and has an elongated shape along the first beam direction. In case of a transducer having a frequency of 1 MHz, the first zone is for example a region of the medium having a length of 13 mm in the first beam direction and a width of 2 mm in orthogonal directions perpendicular to the first beam direction.
A second transducer receiving a second signal of a second amplitude so that to generate a second beam of a second ultrasound wave inside a medium towards a second beam direction produces a second zone of high pressure inside the medium, i.e. a second zone of maximum acoustic power or intensity. The second zone is substantially centered on the second acoustic focal point and has an elongated shape along the second beam direction. The second zone is similar to the first zone, and it has for example the same size as the first zone, but it is elongated in the second beam direction.
In case of a single beam focused on the acoustic focal point, the first zone corresponds to a region of the medium wherein the cavitation occurs if the first signal s1 has a first amplitude greater than a predetermined amplitude. This first zone is quite large and elongated. Moreover, the cavitation inside this region is not stable: cavitation bubbles appear and collapse at various positions inside the volume. These positions of the cavitation bubbles seem to move inside the region, and not to be equally spatially spread inside said region.
In case of non coaxial and confocal dual beams, the first and second zones intersect in a region of interest around the point on which the first and second acoustic focal points are superposed to each other, said region of interest having a reduced size compared to the size of said first zone or said second zone.
It is then difficult to accurately superpose the two acoustic focal points of two separate transducers (i.e. to focus the ultrasound beams generated by two transducers on a same focal point P) and more precisely to superpose them on a target point of the region of interest (i.e. to superpose the focal point P on the target point of the region of interest).
The transducers must be moved accordingly. Furthermore, for nonlinear transducers and/or nonlinear acoustic regimen, changing the amplitude of the signals influences or modifies the position of the acoustic focal points. Therefore, such tuning may be complex in practice.